- Email: [email protected]
Hypofrontality in subjects at high genetic risk of schizophrenia with depressive symptoms
Journal of Affective Disorders 109 (2008) 99 – 106 www.elsevier.com/locate/jad
Research report
Hypofrontality in subjects at high genetic risk of schizophrenia with depressive symptoms H.C. Whalley ⁎, L. Mowatt, A.C. Stanfield, J. Hall, E.C. Johnstone, S.M. Lawrie, A.M. McIntosh Division of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, Scotland, UK Received 8 October 2007; received in revised form 15 November 2007; accepted 15 November 2007 Available online 4 March 2008
Abstract Background: Subjects at high risk of schizophrenia for genetic reasons were found to demonstrate increased levels of depressive symptoms compared to controls. The current study sought to investigate the neural correlates of depression in these subjects. We hypothesised abnormal activation of dorsolateral prefrontal regions in those at high risk with depression. Methods: Depression was rated according to DSM-IV criteria. FMRI data was available from 90 high risk subjects, comprising 78 not depressed (HRD−) and 12 depressed (HRD+) subjects. Activation during the Hayling Sentence Completion Task was compared to 25 healthy control subjects without depression. Results: The HRD+ group demonstrated reduced activation of the right middle/superior frontal gyrus compared to both healthy controls and the HRD− group. Increased left superior temporal gyrus activation was also found in the HRD+ group versus the HRD− group. These results survived controlling for the presence of positive psychotic symptoms at the time of the scan. Conclusion: Reduced activation of dorsolateral prefrontal regions, widely reported in established schizophrenia and seen here in people at high familial risk with depressive features, may be related to the presence of affective symptoms of the disorder rather than to the presence of positive psychotic symptoms. Since studies have indicated that depressive symptoms antecede illness, these findings may be relevant to the early features of developing psychosis. © 2007 Elsevier B.V. All rights reserved. Keywords: fMRI; Depression; Schizophrenia; High risk
1. Introduction Abnormal activation of dorsolateral prefrontal regions in response to tasks involving high cognitive ⁎ Corresponding author. Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Morningside Park, Edinburgh, EH10 5HF, UK. Tel.: +44 131 537 6530; fax: +44 131 537 6531. E-mail address: [email protected] (H.C. Whalley). 0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.11.009
demand has been widely but not invariably reported in the schizophrenia literature (Andreasen et al., 1997; Ingvar and Franzen, 1974; Menon et al., 2001; Perlstein et al., 2001; Weinberger and Berman, 1996; Weinberger et al., 1986). Most studies report decreased activation, “hypofrontality”, with respect to controls, although hyperfrontality is also reported (Glahn et al., 2005) as well as functional deficits in other regions of both the frontal cortex and other brain regions (Lawrie et al., 2002). The apparent inconsistency in the literature may be due to
100
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
clinical heterogeneity, differing pathophysiological mechanisms, or the confounding effects of medication or intercurrent illness. Evidence from studies of unaffected relatives is also somewhat contradictory, although the most common prefrontal cortical response is of hyperactivation (Callicott et al., 2003; Seidman et al., 2006; Thermenos et al., 2004). This has been interpreted as a sign that relatives show a greater level of response to a given cognitive load than unaffected controls, reflecting greater cortical inefficiency (Callicott et al., 2003). In the first prospective study of unaffected subjects at high risk of schizophrenia using the Hayling Sentence Completion Task (Whalley et al., 2004), we found no evidence of abnormal dorsolateral prefrontal response when comparing high risk subjects versus controls, when comparing those with and without positive psychotic symptoms (Whalley et al., 2004) or when comparing those who developed schizophrenia with those that did not (Whalley et al., 2006). This suggests that hypofrontality of dorsolateral prefrontal cortex is not invariably associated with schizophrenia, psychotic symptoms or with increased genetic liability to schizophrenia. This raises the possibility that hypofrontality is associated with a common but as yet unidentified clinical feature in individuals with schizophrenia. Hypofrontality is widely reported in depression (Fitzgerald et al., 2006a; Mayberg et al., 1999; Siegle et al., 2007; Whalley et al., 2004), during both resting state studies and cognitive activation paradigms (Fitzgerald et al., 2006b). Hypofrontality of the dorsolateral prefrontal cortex has also been reported following tryptophan depletion (Bremner et al., 1997) and some, but not all studies, report an increase in dorsolateral prefrontal hypoactivations following antidepressant treatment (Mayberg et al., 2002). Depression is a common symptom before (Owens et al., 2005), during (Wassink et al., 1999) and after an episode of schizophrenia (an der Heiden et al., 2005). In families multiply affected by schizophrenia, there is also evidence for an increased prevalence of depression in never-psychotic relatives (St Clair et al., 1990) and recent evidence suggests the presence of common susceptibility genes for both disorders (Hashimoto et al., 2006). Depression may therefore be part of an extended phenotype, related to increased susceptibility to schizophrenia, but representing an intermediate stage or alternative endpoint of increased genetic risk. Since depression is associated both with hypofrontality of dorsolateral prefrontal cortex and with psychosis, its presence or absence may explain the inconsistency observed in many functional imaging studies of people with schizophrenia.
This study takes advantage of the extensive database of the Edinburgh High Risk Study (EHRS) (Hodges et al., 1999; Johnstone et al., 2000, 2005) in order to examine the effects of depressive symptomatology during fMRI task activation. The EHRS examined young adults at enhanced genetic risk of schizophrenia over a ten year period. The high risk subjects were compared with a group of healthy controls with no family history of psychotic illness and were assessed at 18 month intervals in psychopathological, neuropsychological, and neuroimaging terms. Out of the 163 high risk subjects and 36 controls on which data was collected, 21 high risk and no controls developed schizophrenia. It was evident from early on that the high risk participants had more non-psychotic symptomatology than the controls, including depression (Johnstone et al., 2000), which persisted to later assessments (Owens et al., 2005). We therefore applied DSM-IV (American Psychiatric Association) criteria to all of those subjects with depressive features on the PSE and the results of these findings are presented in the current report. 2. Methods and materials 2.1. Subject details Participants were selected on the basis of being aged between 16 and 25 years when first recruited (1994– 1999), and having two or more first or second degree relatives with schizophrenia. The control group had no known relatives with a psychotic illness. This was a longitudinal study and participants were assessed at approximate intervals of 12–18 months. At the time of recruitment, all participants regarded themselves as being in good health and functioning well. For further details regarding recruitment of the original sample (Hodges et al., 1999). All subjects were supplied with detailed written information regarding the study and provided written informed consent. The study was approved by the Psychiatry and Clinical Psychology subcommittee of the Lothian research ethics committee. This report presents fMRI results obtained during the second phase of the study (1999–2004) when functional imaging was introduced into the protocol. A total of 96 high risk subjects and 26 controls underwent an fMRI scan. All subjects also underwent a structured psychiatric interview (the Present State Examination, Wing et al., 1974) at the time of the scan to determine the presence of psychotic, affective and other symptoms. This interview was carefully recorded and videotaped and subsequently used to apply DSM-IV criteria for depression. One control was found to meet criteria for
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106 Table 1 Demographic details
Mean age (std dev) Gender (male:female) Handedness (R:L:A) Psychotic symptoms⁎ (N:Y)
Controls (n = 25)
HRD− (n = 78)
HRD+ (n = 12)
26.5 (2.7) 16:9 21:3:1 25:0
26.2 (3.4) 37:41 66:9:2 52:26
25.9 (2.9) 5:7 9:2:1 4:8
⁎p = 0.027.
depression and for the purposes of this study was excluded from further analysis. Three high risk subjects were also excluded from further analysis due to minor vascular malformations and a temporal lobe cyst, and a further four high risk subjects were excluded due to movement artefact leaving 90 high risk and 25 control fMRI scans. Twelve high risk subjects were found to meet criteria for depression (‘HRD+’) at any assessment (9 at the time of the scan), the remaining 78 subjects did not (HRD−). Details are presented in Table 1. 2.2. Scanning procedure Imaging was carried out at the Brain Imaging Research Centre (BIRC) for Scotland on a GE 1.5 T Signa scanner (GE Medical, Milwaukee, USA). The imaging protocol consisted of a localiser scan, followed by a T2weighted fast spin-echo sequence, and a structural T1 weighted sequence followed by the functional imaging paradigms. Axial gradient-echo planar images (EPI) (TR/TE = 4000/40 ms; matrix = 64 × 128; field of view = 220 × 440 mm) were acquired continually. Thirty eight contiguous 5-mm slices aligned to the anterior and posterior commissure were acquired within each TR period. Each acquisition was run for 204 volumes, of which the first four volumes were discarded. 2.3. Experiment Participants performed the verbal initiation section of the Hayling sentence completion test in the scanner as described previously (Whalley et al., 2004). Subjects were shown sentences with the last word missing and were asked to silently think of an appropriate word to complete the sentence and press a button when they had done so. Sentences were presented in blocks of fixed difficulty, determined by the range of suitable words suggested by the sentence context, of which there were four levels. Each block lasted 40 s and included 8 sentences. Sentences were presented for a period of 3 s followed by a fixation cross for 2 s and subjects could
101
respond at any time until the next sentence appeared. The rest condition consisted of viewing a screen of white circles on a black background for 40 s. The order of the blocks was pseudo-random, and each block was repeated four times. Immediately after scanning, subjects were given the same sequence of sentences on paper and requested to complete each sentence with the word they first thought of in the scanner. ‘Word appropriateness’ scores were determined from the word frequency list of sentence completion norms (Bloom and Fischler, 1980). During the same scanning session a further functional imaging study was performed, the results of which are not discussed here. 2.4. Image processing and analysis Scan analysis was performed using the standard SPM approach in SPM2 (The Wellcome Department of Cognitive Neurology and collaborators, Institute of Neurology, London, http://www.fil.ion.ucl.ac.uk/spm/) running in Matlab (The MathWorks, Natick, MA, USA). Briefly, EPI volumes were realigned to the mean volume in the series, normalised to a study specific EPI template (comprising 121 participants of the EHRS) and spatially smoothed with a 6 × 6 × 6 mm3 FWHM Gaussian filter. Statistical analysis was performed using the general linear model approach as implemented in SPM. At the individual subject level the data was modelled with 5 conditions (the four difficulty levels and the rest condition), each modelled by a boxcar convolved with a synthetic haemodynamic response function. The estimates of the subject’s movement during the scan were also entered as ‘covariates of no interest’. Contrasts were constructed to examine all four sentence completion conditions versus rest, and areas of increasing activation with increasing task difficulty (the parametric contrast). For each contrast of interest (sentence completion versus rest, and parametric effects) one contrast image per subject was entered into a second level random effects analysis to examine differences in activation between the groups (controls, HRD− and HRD+ using ANOVA). Statistical maps were thresholded at a level of p = 0.005 uncorrected, and regions were considered significant at p b 0.05 cluster level corrected for multiple comparisons. All p values quoted in the text are at the corrected cluster level. Since we had prior hypotheses regarding dorsolateral prefrontal cortex involvement we imposed an anatomically defined bilateral small volume correction (SVC) for the superior and middle frontal gyrus using the Wake Forest University (WFU) PickAtlas software (http://www.fmri.wfubmc.edu/download.htm). Coordinates were converted from MNI (Montreal
102
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
Table 2 Behavioural measures Group
Mean word appropriateness (std dev)
Mean reaction time (ms) (std dev)
Constraint levels
Low
Med low
Med high
High
Low
Med low
Med high
High
Controls HRD− HRD+
6.34 (1.19) 6.39 (1.00) 6.41 (0.86)
3.25 (0.51) 3.23 (0.58) 3.39 (0.57)
1.97 (0.31) 1.99 (0.36) 2.04 (0.42)
1.10 (0.07) 1.12 (0.08) 1.16 (0.13)
2602 (519) 2490 (566) 2727 (760)
2475 (587) 2400 (609) 2567 (694)
2369 (592) 2264 (621) 2474 (730)
2294 (621) 2272 (626) 2476 (705)
Constraint levels high to low represent increasing difficulty. Higher word appropriateness scores indicate worse performance.
Neurological Institute) to Talairach coordinates using a non-linear transformation (http://www.mrc-cbu.cam.ac. uk/Imaging). 3. Results 3.1. Demographic details and behavioural measures There were no statistically significant differences in age, gender, handedness or behavioural measures (word appropriateness or reaction time) between the subject groups (Tables 1 and 2). There was however a significant difference between high risk groups with and without depression for the reporting of psychotic symptoms at the time of the scan, with significantly more psychotic symptoms reported in the depressed group ( p = 0.027). 3.2. Sentence completion versus rest The within group maps indicated regions commonly activated in this type of tasks and are consistent with previous results (Whalley et al., 2004). The main areas
of activation were the left precentral gyrus, inferior frontal gyrus, medial/superior frontal gyrus, middle temporal gyrus, cerebellum and occipital lobes bilaterally. Increased activation was found in the left posterior superior temporal gyrus in the HRD+ group versus HRD− (see Table 3, Fig. 1). This was also seen between the HRD + group versus controls, but did not reach statistical significance ( p = 0.158). 3.3. Parametric contrast In general the within group maps for the parametric contrast indicated involvement of areas consistent with previous results (Whalley et al., 2004), i.e. increased activation with increased difficulty in the left superior/ medial frontal gyrus, inferior frontal gyrus and cerebellum. Decreased activation was found in the right middle/ superior frontal gyrus (BA8/9) in the HRD+ group versus both the HRD− group and controls (Table 3, Fig. 2). Decreased right inferior parietal lobule activation was also found in the HRD+ group relative to controls.
Table 3 Between groups random effects analysis P value
Extent
Z
Peak height
Sentence completion versus rest Controls (n = 25) N High risk with depression (n = 12): n/s Controls (n = 25) b High risk with depression (n = 12): 0.158 263 3.66 − 51 − 30 18 High risk no depression (n = 78) N High risk with depression (n = 12): n/s High risk no depression (n = 78) b High risk with depression (n = 12): 0.048a 357 3.73 − 51 − 30 22 Parametric contrast: Controls (n = 25) N High risk with depression (n = 12): 0.010a,b 311 4.21 26 43 42 0.001 648 4.35 44 −56 51 0.060 303 4.68 6 −4 0 Controls (n = 25) b High risk with depression (n = 12): n/s High risk no depression (n = 78) N High risk with depression (n = 12): 0.015a,b 279 3.67 28 24 52 High risk no depression (n = 78) b High risk with depression (n = 12): n/s a
Region
Left superior temporal gyrus/Sylvian fissure
Left superior temporal gyrus/Sylvian fissure
Right middle/superior frontal gyrus (BA8/9) Right inferior parietal lobule (BA7/40) Right thalamus
Right middle/superior frontal gyrus (BA8/9)
Results which remained significant after controlling for the presence of psychotic symptoms at the time of the scan. Small volume correction.
b
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
103
Fig. 1. Sentence completion versus rest. (a) Differential activation between high risk with depression N high risk without depression in left superior temporal gyrus/Sylvian fissure ( p = 0.048) overlaid on canonical T1 image. Maps thresholded at 0.005 p uncorrected, KE = 300 voxels. (b) Plots of contrast estimates, 1 = control group, 2 = high risk without depression, 3 = high risk with depression. ⁎ indicates significant differences ( p b 0.05 corrected cluster level).
3.4. Controlling for psychotic symptoms In order to ascertain which significant differences remained between depressed and non-depressed subjects after the model was adjusted for the presence of psychotic symptoms, all analyses were re-run with psychotic symptoms (yes/no) included in the ANCOVA
model. Decreased activation of the HRD+ group relative to the two other groups was in the right middle/superior frontal gyrus for the parametric contrast ( p = 0.043, p = 0.004 in comparison with controls and HRD− respectively), and increased activation of the HRD+ group relative to the HRD− group in the left superior temporal gyrus for sentence completion versus rest ( p = 0.049).
Fig. 2. Parametric contrast. (a) Differential activation between controls N high risk with depression in right middle/superior frontal gyrus ( p = 0.01) overlaid on canonical T1 image. Maps thresholded at 0.005 p uncorrected, KE = 300 voxels. (b) Plots of contrast estimates, 1 = control group, 2 = high risk without depression, 3 = high risk with depression. ⁎ indicates significant differences ( p b 0.05 corrected cluster level with prefrontal small volume correction).
104
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
3.5. Excluding subjects who were not depressed at the time of the scan Out of the 12 subjects who met criteria for depression at some stage, 3 subjects were found not to meet criteria at the time of the scan. Analysis was performed excluding these three subjects and the following result remained significant; decreased activation of the HRD+ group relative to the control group in the right middle/ superior frontal gyrus for the parametric contrast ( p = 0.012). In comparison to the HRD− group this results reduced to a trend level significance ( p = 0.078), however a plot of the parameter estimates indicated (as seen in Fig. 2) that the HRD− group was intermediate to the other two groups. 4. Discussion The focus of the current study was to investigate the neural correlates of depression in subjects at high genetic risk of schizophrenia. We demonstrated abnormal prefrontal lobe functioning in high risk subjects who met standardised criteria for depression, in line with our hypothesis. Additional activation differences were also demonstrated in the lateral temporal cortex. These findings remained significant after controlling for the presence of psychotic symptoms at the time of the scan and indicated abnormal functioning of the dorsolateral prefrontal cortex in this cohort was related to depressive features of the illness. It has previously been suggested that dysfunction of the dorsolateral prefrontal cortex is potentially relevant to many forms of psychopathology, including both schizophrenia and depression (see Roberts et al., 1998). Indeed a loss of the normal pattern of activity of the prefrontal cortex has been extensively reported in both the literature on schizophrenia and depression (Andreasen et al 1997; Ingvar and Franzen 1974; Menon et al 2001; Perlstein et al 2001; Weinberger and Berman 1996; Weinberger et al 1986; Merriam et al., 1999; Sweeney et al., 1998; Medved et al., 2001). Although there are at present a relatively few functional imaging studies of relatives of patients with schizophrenia, there is increasing evidence to suggest abnormal dorsolateral prefrontal cortex activity in those at high genetic risk for the disorder (Callicott et al., 2003; Seidman et al., 2006; Thermenos et al., 2004). In our previous report examining clinical aspects of the same cohort we report elevated levels of depression in those who subsequently progress to illness and have suggested that such affective features may be central to the illness process (Owens et al., 2005), and may relate to cognitive deficits reported in those at high risk of the disorder.
Although existing evidence supports an association between hypofrontality, depression and cognitive impairment, there is remaining uncertainty regarding the direction of the association between depressive symptoms and cognition. It should be noted however that in the high risk literature the abnormal prefrontal cortex response is most consistently reported as hyperfrontality (Callicott et al., 2003; Seidman et al., 2006). Such findings are often interpreted as a functional inefficiency of the region, or as a compensatory response to maintain adequate levels of performance (Fusar-Poli et al., 2007). In the current study however we report hypofrontality in the high risk subjects with depression. As in the established disorder, the directionality of response (hyper- or hypofrontality) is proposed to relate to perceived task difficulty and ensuing performance levels (the inverted ‘U’ see (Manoach, 2003)). We speculate that although no significant performance differences were found between the groups, these subjects consistently demonstrated the highest reaction times and highest (worse) word appropriateness scores at all levels of task difficulty, hence this pattern of decreased response may indicate the beginnings of a failure of response in these more symptomatic subjects. Increased task related activity in the superior temporal gyrus was also found in subjects at high risk of schizophrenia with depressive features. The prefrontal cortex and superior temporal gyrus have previously been shown to interact, with greater prefrontal activation leading to suppression of activity in the superior temporal gyrus (Lawrie et al., 2002). Increased superior temporal gyral activity has also been shown in subjects with depression who demonstrated a hypofrontal response to the Tower of London Task (Goethals et al., 2005). The authors of the study suggest that this response is compensatory for the dysfunction within the prefrontal cortex. In conclusion, dorsolateral prefrontal cortex dysfunction was associated with depressive features in this high risk cohort. Since we have previously reported elevated levels of depression in those who subsequently become ill, these findings may have potential relevance for the study of the early features of developing psychosis.
Role of funding source The study was funded by an MRC programme grant. Dr. Lawrie and Dr. Whalley are supported by a charitable donation from the Dr. Mortimer and Theresa Sackler Foundation. Dr. McIntosh is supported by the Health Foundation. Conflict of interest None of the authors have any conflicts of interest to declare.
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
Acknowledgement The study was funded by an MRC programme grant. Dr. Lawrie and Dr. Whalley are supported by a charitable donation from the Dr. Mortimer and Theresa Sackler Foundation. Dr. McIntosh is supported by the Health Foundation. Scanning was carried out at the Brain Imaging Research Centre (BIRC) for Scotland. Both BIRC and the Centre for Functional Imaging studies (CFIS) are funded by the Scottish Higher Education Funding Council (SHEFC). We would also like to thank those involved in subject recruitment, the radiographers, and the study participants. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jad.2007. 11.009. References an der Heiden, W., Könnecke, R., Maurer, K., Ropeter, D., Häfner, H., 2005. Depression in the long-term course of schizophrenia. European Archives of Psychiatry and Clinical Neuroscience 255, 174–184. Andreasen, N.C., O'Leary, D.S., Flaum, M., Nopoulos, P., Watkins, G.L., Boles Ponto, L.L., Hichwa, R.D., 1997. Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naive patients. Lancet 349, 1730–1734. Bloom, P.A., Fischler, I., 1980. Completion norms for 329 sentence contexts. Memory and Cogntion 8, 631–642. Bremner, J.D., Innis, R.B., Salomon, R.M., Staib, L.H., Ng, C.K., Miller, H.L., Bronen, R.A., Krystal, J.H., Duncan, J., Rich, D., Price, L.H., Malison, R., Dey, H., Soufer, R., Charney, D.S., 1997. Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. Archives of General Psychiatry 364–374. Callicott, J.H., Egan, M.F., Mattay, V.S., Bertolino, A., Bone, A.D., Verchinksi, B., Weinberger, D.R., 2003. Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. American Journal of Psychiatry 160, 709–719. Fitzgerald, P.B., Oxley, T.J., Laird, A.R., Kulkarni, J., Egan, G.F., Daskalakis, Z.J., 2006a. An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression. Psychiatry Research 148, 33–45. Fitzgerald, P.B., Oxley, T.J., Laird, A.R., Kulkarni, J., Egan, G.F., Daskalakis, Z.J., 2006b. An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression. Psychiatry Research 148, 33–45. Fusar-Poli, P., Perez, J., Broome, M., Borgwardt, S., Placentino, A., Caverzasi, E., Cortesi, M., Veggiotti, P., Politi, P., Barale, F., McGuire, P., 2007. Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews 31, 465–484. Glahn, D.C., Ragland, J.D., Abramoff, A., Barrett, J., Laird, A.R., Bearden, C.E., Velligan, D.I., 2005. Beyond hypofrontality:
105
a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Human Brain Mapping 25, 60–69. Goethals, I., Audenaert, K., Jacobs, F., Van de Wiele, C., Ham, H., Pyck, H., Vandierendonck, A., Van Heeringen, C., Dierckx, R., 2005. Blunted prefrontal perfusion in depressed patients performing the Tower of London task. Psychiatry Research 139, 31–40. Hashimoto, R., Numakawa, T., Ohnishi, T., Kumamaru, E., Yagasaki, Y., Ishimoto, T., Mori, T., Nemoto, K., Adachi, N., Izumi, A., Chiba, S., Noguchi, H., Suzuki, T., Iwata, N., Ozaki, N., Taguchi, T., Kamiya, A., Kosuga, A., Tatsumi, M., Kamijima, K., Weinberger, D.R., Sawa, A., Kunugi, H., 2006. Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Human molecular genetics 15, 3024–3033. Hodges, A., Byrne, M., Grant, E., Johnstone, E., 1999. People at risk of schizophrenia. Sample characteristics of the first 100 cases in the Edinburgh high-risk study. British Journal of Psychiatry 174, 547–553. Ingvar, D.H., Franzen, G., 1974. Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia. Acta Psychiatrica Scandinavica 50, 425–462. Johnstone, E.C., Abukmeil, S.S., Byrne, M., Clafferty, R., Grant, E., Hodges, A., Lawrie, S.M., Owens, D.G., 2000. Edinburgh high risk study—findings after four years: demographic, attainment and psychopathological issues. Schizophrenia Research 46, 1–15. Johnstone, E.C., Ebmeier, K.P., Miller, P., Owens, D.G., Lawrie, S.M., 2005. Predicting schizophrenia: findings from the Edinburgh highrisk study. British Journal of Psychiatry 186, 18–25. Lawrie, S.M., Buechel, C., Whalley, H.C., Frith, C.D., Friston, K.J., Johnstone, E.C., 2002. Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biological Psychiatry 51, 1008–1011. Manoach, D.S., 2003. Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophrenia Research 60, 285–298. Mayberg, H.S., Liotti, M., Brannan, S.K., McGinnis, S., Mahurin, R.K., Jerabek, P.A., Silva, J.A., Tekell, J.L., Martin, C.C., Lancaster, J.L., Fox, P.T., 1999. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. American Journal of Psychiatry 156, 675–682. Mayberg, H.S., Silva, J.A., Brannan, S.K., Tekell, J.L., Mahurin, R.K., McGinnis, S., Jerabek, P.A., 2002. The functional neuroanatomy of the placebo effect. American Journal of Psychiatry 159, 728–737. Medved, V., Petrovi, R., Igum, V., Szirovicza, L., Hotujac, L., 2001. Similarities in the pattern of regional brain dysfunction in negative schizophrenia and unipolar depression: a single photon emissioncomputed tomography and auditory evoked potentials study. Progress in Neuro Psychopharmacology and Biological Psychiatry 25, 993–1009. Menon, V., Anagnoson, R.T., Mathalon, D.H., Glover, G.H., Pfefferbaum, A., 2001. Functional neuroanatomy of auditory working memory in schizophrenia: relation to positive and negative symptoms. Neuroimage 13, 433–446. Merriam, E.P., Thase, M.E., Haas, G.L., Keshavan, M.S., Sweeney, J.A., 1999. Prefrontal cortical dysfunction in depression determined by Wisconsin card sorting test performance. American Journal of Psychiatry 156, 780–782. Owens, D.G.C., Miller, P., Lawrie, S.M., Johnstone, E.C., 2005. Pathogenesis of schizophrenia: a psychopathological perspective. British Journal of Psychiatry 186, 386–393. Perlstein, W.M., Carter, C.S., Noll, D.C., Cohen, J.D., 2001. Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. American Journal of Psychiatry 158, 1105–1113.
106
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
Roberts, A.C., Robbins, T.W., Weiskrantz, L., 1998. The Prefrontal Cortex: Executive and Cognitive Functions. Oxford University Press. Seidman, L.J., Thermenos, H.W., Poldrack, R.A., Peace, N.K., Koch, J.K., Faraone, S.V., Tsuang, M.T., 2006. Altered brain activation in dorsolateral prefrontal cortex in adolescents and young adults at genetic risk for schizophrenia: an fMRI study of working memory. Schizophrenia Research 85, 58–72. Siegle, G.J., Thompson, W., Carter, C.S., Steinhauer, S.R., Thase, M.E., 2007. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biological Psychiatry 61, 198–209. St Clair, D., Blackwood, D., Muir, W., Carothers, A., Walker, M., Spowart, G., Gosden, C., Evans, H.J., 1990. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336, 13–16. Sweeney, J.A., Strojwas, M.H., Mann, J.J., Thase, M.E., 1998. Prefrontal and cerebellar abnormalities in major depression: evidence from oculomotor studies. Biological Psychiatry 43, 584–594. Thermenos, H.W., Seidman, L.J., Breiter, H., Goldstein, J.M., Goodman, J.M., Poldrack, R., Faraone, S.V., Tsuang, M.T., 2004. Functional magnetic resonance imaging during auditory verbal working memory in nonpsychotic relatives of persons with schizophrenia: a pilot study. Biological Psychiatry 55, 490–500.
Wassink, T.H., Flaum, M., Nopoulos, P., Andreasen, N.C., 1999. Prevalence of depressive symptoms early in the course of schizophrenia. American Journal of Psychiatry 315–316. Weinberger, D.R., Berman, K.F., 1996. Prefrontal function in schizophrenia: confounds and controversies. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 351, 1495–1503. Weinberger, D.R., Berman, K.F., Zec, R.F., 1986. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence.[see comment]. Archives of General Psychiatry 43, 114–124. Whalley, H.C., Simonotto, E., Flett, S., Marshall, I., Ebmeier, K.P., Owens, D.G., Goddard, N.H., Johnstone, E.C., Lawrie, S.M., 2004. fMRI correlates of state and trait effects in subjects at genetically enhanced risk of schizophrenia. Brain 127, 478–490. Whalley, H.C., Simonotto, E., Moorhead, T.W., McIntosh, A.M., Marshall, I., Owens, D.G.C., Goddard, N.H., Johnstone, E.C., Lawrie, S.M., 2006. Functional imaging as a predictor of schizophrenia. Biological Psychiatry 60, 454–462. Wing, J.K., Cooper, J.E., Sartorius, N., 1974. The Description and Classification of Psychiatric Symptoms. An Instruction Manual for the PSE and CATEGO Systems. Cambridge University Press, Cambridge.
Research report
Hypofrontality in subjects at high genetic risk of schizophrenia with depressive symptoms H.C. Whalley ⁎, L. Mowatt, A.C. Stanfield, J. Hall, E.C. Johnstone, S.M. Lawrie, A.M. McIntosh Division of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, Scotland, UK Received 8 October 2007; received in revised form 15 November 2007; accepted 15 November 2007 Available online 4 March 2008
Abstract Background: Subjects at high risk of schizophrenia for genetic reasons were found to demonstrate increased levels of depressive symptoms compared to controls. The current study sought to investigate the neural correlates of depression in these subjects. We hypothesised abnormal activation of dorsolateral prefrontal regions in those at high risk with depression. Methods: Depression was rated according to DSM-IV criteria. FMRI data was available from 90 high risk subjects, comprising 78 not depressed (HRD−) and 12 depressed (HRD+) subjects. Activation during the Hayling Sentence Completion Task was compared to 25 healthy control subjects without depression. Results: The HRD+ group demonstrated reduced activation of the right middle/superior frontal gyrus compared to both healthy controls and the HRD− group. Increased left superior temporal gyrus activation was also found in the HRD+ group versus the HRD− group. These results survived controlling for the presence of positive psychotic symptoms at the time of the scan. Conclusion: Reduced activation of dorsolateral prefrontal regions, widely reported in established schizophrenia and seen here in people at high familial risk with depressive features, may be related to the presence of affective symptoms of the disorder rather than to the presence of positive psychotic symptoms. Since studies have indicated that depressive symptoms antecede illness, these findings may be relevant to the early features of developing psychosis. © 2007 Elsevier B.V. All rights reserved. Keywords: fMRI; Depression; Schizophrenia; High risk
1. Introduction Abnormal activation of dorsolateral prefrontal regions in response to tasks involving high cognitive ⁎ Corresponding author. Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Morningside Park, Edinburgh, EH10 5HF, UK. Tel.: +44 131 537 6530; fax: +44 131 537 6531. E-mail address: [email protected] (H.C. Whalley). 0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.11.009
demand has been widely but not invariably reported in the schizophrenia literature (Andreasen et al., 1997; Ingvar and Franzen, 1974; Menon et al., 2001; Perlstein et al., 2001; Weinberger and Berman, 1996; Weinberger et al., 1986). Most studies report decreased activation, “hypofrontality”, with respect to controls, although hyperfrontality is also reported (Glahn et al., 2005) as well as functional deficits in other regions of both the frontal cortex and other brain regions (Lawrie et al., 2002). The apparent inconsistency in the literature may be due to
100
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
clinical heterogeneity, differing pathophysiological mechanisms, or the confounding effects of medication or intercurrent illness. Evidence from studies of unaffected relatives is also somewhat contradictory, although the most common prefrontal cortical response is of hyperactivation (Callicott et al., 2003; Seidman et al., 2006; Thermenos et al., 2004). This has been interpreted as a sign that relatives show a greater level of response to a given cognitive load than unaffected controls, reflecting greater cortical inefficiency (Callicott et al., 2003). In the first prospective study of unaffected subjects at high risk of schizophrenia using the Hayling Sentence Completion Task (Whalley et al., 2004), we found no evidence of abnormal dorsolateral prefrontal response when comparing high risk subjects versus controls, when comparing those with and without positive psychotic symptoms (Whalley et al., 2004) or when comparing those who developed schizophrenia with those that did not (Whalley et al., 2006). This suggests that hypofrontality of dorsolateral prefrontal cortex is not invariably associated with schizophrenia, psychotic symptoms or with increased genetic liability to schizophrenia. This raises the possibility that hypofrontality is associated with a common but as yet unidentified clinical feature in individuals with schizophrenia. Hypofrontality is widely reported in depression (Fitzgerald et al., 2006a; Mayberg et al., 1999; Siegle et al., 2007; Whalley et al., 2004), during both resting state studies and cognitive activation paradigms (Fitzgerald et al., 2006b). Hypofrontality of the dorsolateral prefrontal cortex has also been reported following tryptophan depletion (Bremner et al., 1997) and some, but not all studies, report an increase in dorsolateral prefrontal hypoactivations following antidepressant treatment (Mayberg et al., 2002). Depression is a common symptom before (Owens et al., 2005), during (Wassink et al., 1999) and after an episode of schizophrenia (an der Heiden et al., 2005). In families multiply affected by schizophrenia, there is also evidence for an increased prevalence of depression in never-psychotic relatives (St Clair et al., 1990) and recent evidence suggests the presence of common susceptibility genes for both disorders (Hashimoto et al., 2006). Depression may therefore be part of an extended phenotype, related to increased susceptibility to schizophrenia, but representing an intermediate stage or alternative endpoint of increased genetic risk. Since depression is associated both with hypofrontality of dorsolateral prefrontal cortex and with psychosis, its presence or absence may explain the inconsistency observed in many functional imaging studies of people with schizophrenia.
This study takes advantage of the extensive database of the Edinburgh High Risk Study (EHRS) (Hodges et al., 1999; Johnstone et al., 2000, 2005) in order to examine the effects of depressive symptomatology during fMRI task activation. The EHRS examined young adults at enhanced genetic risk of schizophrenia over a ten year period. The high risk subjects were compared with a group of healthy controls with no family history of psychotic illness and were assessed at 18 month intervals in psychopathological, neuropsychological, and neuroimaging terms. Out of the 163 high risk subjects and 36 controls on which data was collected, 21 high risk and no controls developed schizophrenia. It was evident from early on that the high risk participants had more non-psychotic symptomatology than the controls, including depression (Johnstone et al., 2000), which persisted to later assessments (Owens et al., 2005). We therefore applied DSM-IV (American Psychiatric Association) criteria to all of those subjects with depressive features on the PSE and the results of these findings are presented in the current report. 2. Methods and materials 2.1. Subject details Participants were selected on the basis of being aged between 16 and 25 years when first recruited (1994– 1999), and having two or more first or second degree relatives with schizophrenia. The control group had no known relatives with a psychotic illness. This was a longitudinal study and participants were assessed at approximate intervals of 12–18 months. At the time of recruitment, all participants regarded themselves as being in good health and functioning well. For further details regarding recruitment of the original sample (Hodges et al., 1999). All subjects were supplied with detailed written information regarding the study and provided written informed consent. The study was approved by the Psychiatry and Clinical Psychology subcommittee of the Lothian research ethics committee. This report presents fMRI results obtained during the second phase of the study (1999–2004) when functional imaging was introduced into the protocol. A total of 96 high risk subjects and 26 controls underwent an fMRI scan. All subjects also underwent a structured psychiatric interview (the Present State Examination, Wing et al., 1974) at the time of the scan to determine the presence of psychotic, affective and other symptoms. This interview was carefully recorded and videotaped and subsequently used to apply DSM-IV criteria for depression. One control was found to meet criteria for
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106 Table 1 Demographic details
Mean age (std dev) Gender (male:female) Handedness (R:L:A) Psychotic symptoms⁎ (N:Y)
Controls (n = 25)
HRD− (n = 78)
HRD+ (n = 12)
26.5 (2.7) 16:9 21:3:1 25:0
26.2 (3.4) 37:41 66:9:2 52:26
25.9 (2.9) 5:7 9:2:1 4:8
⁎p = 0.027.
depression and for the purposes of this study was excluded from further analysis. Three high risk subjects were also excluded from further analysis due to minor vascular malformations and a temporal lobe cyst, and a further four high risk subjects were excluded due to movement artefact leaving 90 high risk and 25 control fMRI scans. Twelve high risk subjects were found to meet criteria for depression (‘HRD+’) at any assessment (9 at the time of the scan), the remaining 78 subjects did not (HRD−). Details are presented in Table 1. 2.2. Scanning procedure Imaging was carried out at the Brain Imaging Research Centre (BIRC) for Scotland on a GE 1.5 T Signa scanner (GE Medical, Milwaukee, USA). The imaging protocol consisted of a localiser scan, followed by a T2weighted fast spin-echo sequence, and a structural T1 weighted sequence followed by the functional imaging paradigms. Axial gradient-echo planar images (EPI) (TR/TE = 4000/40 ms; matrix = 64 × 128; field of view = 220 × 440 mm) were acquired continually. Thirty eight contiguous 5-mm slices aligned to the anterior and posterior commissure were acquired within each TR period. Each acquisition was run for 204 volumes, of which the first four volumes were discarded. 2.3. Experiment Participants performed the verbal initiation section of the Hayling sentence completion test in the scanner as described previously (Whalley et al., 2004). Subjects were shown sentences with the last word missing and were asked to silently think of an appropriate word to complete the sentence and press a button when they had done so. Sentences were presented in blocks of fixed difficulty, determined by the range of suitable words suggested by the sentence context, of which there were four levels. Each block lasted 40 s and included 8 sentences. Sentences were presented for a period of 3 s followed by a fixation cross for 2 s and subjects could
101
respond at any time until the next sentence appeared. The rest condition consisted of viewing a screen of white circles on a black background for 40 s. The order of the blocks was pseudo-random, and each block was repeated four times. Immediately after scanning, subjects were given the same sequence of sentences on paper and requested to complete each sentence with the word they first thought of in the scanner. ‘Word appropriateness’ scores were determined from the word frequency list of sentence completion norms (Bloom and Fischler, 1980). During the same scanning session a further functional imaging study was performed, the results of which are not discussed here. 2.4. Image processing and analysis Scan analysis was performed using the standard SPM approach in SPM2 (The Wellcome Department of Cognitive Neurology and collaborators, Institute of Neurology, London, http://www.fil.ion.ucl.ac.uk/spm/) running in Matlab (The MathWorks, Natick, MA, USA). Briefly, EPI volumes were realigned to the mean volume in the series, normalised to a study specific EPI template (comprising 121 participants of the EHRS) and spatially smoothed with a 6 × 6 × 6 mm3 FWHM Gaussian filter. Statistical analysis was performed using the general linear model approach as implemented in SPM. At the individual subject level the data was modelled with 5 conditions (the four difficulty levels and the rest condition), each modelled by a boxcar convolved with a synthetic haemodynamic response function. The estimates of the subject’s movement during the scan were also entered as ‘covariates of no interest’. Contrasts were constructed to examine all four sentence completion conditions versus rest, and areas of increasing activation with increasing task difficulty (the parametric contrast). For each contrast of interest (sentence completion versus rest, and parametric effects) one contrast image per subject was entered into a second level random effects analysis to examine differences in activation between the groups (controls, HRD− and HRD+ using ANOVA). Statistical maps were thresholded at a level of p = 0.005 uncorrected, and regions were considered significant at p b 0.05 cluster level corrected for multiple comparisons. All p values quoted in the text are at the corrected cluster level. Since we had prior hypotheses regarding dorsolateral prefrontal cortex involvement we imposed an anatomically defined bilateral small volume correction (SVC) for the superior and middle frontal gyrus using the Wake Forest University (WFU) PickAtlas software (http://www.fmri.wfubmc.edu/download.htm). Coordinates were converted from MNI (Montreal
102
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
Table 2 Behavioural measures Group
Mean word appropriateness (std dev)
Mean reaction time (ms) (std dev)
Constraint levels
Low
Med low
Med high
High
Low
Med low
Med high
High
Controls HRD− HRD+
6.34 (1.19) 6.39 (1.00) 6.41 (0.86)
3.25 (0.51) 3.23 (0.58) 3.39 (0.57)
1.97 (0.31) 1.99 (0.36) 2.04 (0.42)
1.10 (0.07) 1.12 (0.08) 1.16 (0.13)
2602 (519) 2490 (566) 2727 (760)
2475 (587) 2400 (609) 2567 (694)
2369 (592) 2264 (621) 2474 (730)
2294 (621) 2272 (626) 2476 (705)
Constraint levels high to low represent increasing difficulty. Higher word appropriateness scores indicate worse performance.
Neurological Institute) to Talairach coordinates using a non-linear transformation (http://www.mrc-cbu.cam.ac. uk/Imaging). 3. Results 3.1. Demographic details and behavioural measures There were no statistically significant differences in age, gender, handedness or behavioural measures (word appropriateness or reaction time) between the subject groups (Tables 1 and 2). There was however a significant difference between high risk groups with and without depression for the reporting of psychotic symptoms at the time of the scan, with significantly more psychotic symptoms reported in the depressed group ( p = 0.027). 3.2. Sentence completion versus rest The within group maps indicated regions commonly activated in this type of tasks and are consistent with previous results (Whalley et al., 2004). The main areas
of activation were the left precentral gyrus, inferior frontal gyrus, medial/superior frontal gyrus, middle temporal gyrus, cerebellum and occipital lobes bilaterally. Increased activation was found in the left posterior superior temporal gyrus in the HRD+ group versus HRD− (see Table 3, Fig. 1). This was also seen between the HRD + group versus controls, but did not reach statistical significance ( p = 0.158). 3.3. Parametric contrast In general the within group maps for the parametric contrast indicated involvement of areas consistent with previous results (Whalley et al., 2004), i.e. increased activation with increased difficulty in the left superior/ medial frontal gyrus, inferior frontal gyrus and cerebellum. Decreased activation was found in the right middle/ superior frontal gyrus (BA8/9) in the HRD+ group versus both the HRD− group and controls (Table 3, Fig. 2). Decreased right inferior parietal lobule activation was also found in the HRD+ group relative to controls.
Table 3 Between groups random effects analysis P value
Extent
Z
Peak height
Sentence completion versus rest Controls (n = 25) N High risk with depression (n = 12): n/s Controls (n = 25) b High risk with depression (n = 12): 0.158 263 3.66 − 51 − 30 18 High risk no depression (n = 78) N High risk with depression (n = 12): n/s High risk no depression (n = 78) b High risk with depression (n = 12): 0.048a 357 3.73 − 51 − 30 22 Parametric contrast: Controls (n = 25) N High risk with depression (n = 12): 0.010a,b 311 4.21 26 43 42 0.001 648 4.35 44 −56 51 0.060 303 4.68 6 −4 0 Controls (n = 25) b High risk with depression (n = 12): n/s High risk no depression (n = 78) N High risk with depression (n = 12): 0.015a,b 279 3.67 28 24 52 High risk no depression (n = 78) b High risk with depression (n = 12): n/s a
Region
Left superior temporal gyrus/Sylvian fissure
Left superior temporal gyrus/Sylvian fissure
Right middle/superior frontal gyrus (BA8/9) Right inferior parietal lobule (BA7/40) Right thalamus
Right middle/superior frontal gyrus (BA8/9)
Results which remained significant after controlling for the presence of psychotic symptoms at the time of the scan. Small volume correction.
b
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
103
Fig. 1. Sentence completion versus rest. (a) Differential activation between high risk with depression N high risk without depression in left superior temporal gyrus/Sylvian fissure ( p = 0.048) overlaid on canonical T1 image. Maps thresholded at 0.005 p uncorrected, KE = 300 voxels. (b) Plots of contrast estimates, 1 = control group, 2 = high risk without depression, 3 = high risk with depression. ⁎ indicates significant differences ( p b 0.05 corrected cluster level).
3.4. Controlling for psychotic symptoms In order to ascertain which significant differences remained between depressed and non-depressed subjects after the model was adjusted for the presence of psychotic symptoms, all analyses were re-run with psychotic symptoms (yes/no) included in the ANCOVA
model. Decreased activation of the HRD+ group relative to the two other groups was in the right middle/superior frontal gyrus for the parametric contrast ( p = 0.043, p = 0.004 in comparison with controls and HRD− respectively), and increased activation of the HRD+ group relative to the HRD− group in the left superior temporal gyrus for sentence completion versus rest ( p = 0.049).
Fig. 2. Parametric contrast. (a) Differential activation between controls N high risk with depression in right middle/superior frontal gyrus ( p = 0.01) overlaid on canonical T1 image. Maps thresholded at 0.005 p uncorrected, KE = 300 voxels. (b) Plots of contrast estimates, 1 = control group, 2 = high risk without depression, 3 = high risk with depression. ⁎ indicates significant differences ( p b 0.05 corrected cluster level with prefrontal small volume correction).
104
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
3.5. Excluding subjects who were not depressed at the time of the scan Out of the 12 subjects who met criteria for depression at some stage, 3 subjects were found not to meet criteria at the time of the scan. Analysis was performed excluding these three subjects and the following result remained significant; decreased activation of the HRD+ group relative to the control group in the right middle/ superior frontal gyrus for the parametric contrast ( p = 0.012). In comparison to the HRD− group this results reduced to a trend level significance ( p = 0.078), however a plot of the parameter estimates indicated (as seen in Fig. 2) that the HRD− group was intermediate to the other two groups. 4. Discussion The focus of the current study was to investigate the neural correlates of depression in subjects at high genetic risk of schizophrenia. We demonstrated abnormal prefrontal lobe functioning in high risk subjects who met standardised criteria for depression, in line with our hypothesis. Additional activation differences were also demonstrated in the lateral temporal cortex. These findings remained significant after controlling for the presence of psychotic symptoms at the time of the scan and indicated abnormal functioning of the dorsolateral prefrontal cortex in this cohort was related to depressive features of the illness. It has previously been suggested that dysfunction of the dorsolateral prefrontal cortex is potentially relevant to many forms of psychopathology, including both schizophrenia and depression (see Roberts et al., 1998). Indeed a loss of the normal pattern of activity of the prefrontal cortex has been extensively reported in both the literature on schizophrenia and depression (Andreasen et al 1997; Ingvar and Franzen 1974; Menon et al 2001; Perlstein et al 2001; Weinberger and Berman 1996; Weinberger et al 1986; Merriam et al., 1999; Sweeney et al., 1998; Medved et al., 2001). Although there are at present a relatively few functional imaging studies of relatives of patients with schizophrenia, there is increasing evidence to suggest abnormal dorsolateral prefrontal cortex activity in those at high genetic risk for the disorder (Callicott et al., 2003; Seidman et al., 2006; Thermenos et al., 2004). In our previous report examining clinical aspects of the same cohort we report elevated levels of depression in those who subsequently progress to illness and have suggested that such affective features may be central to the illness process (Owens et al., 2005), and may relate to cognitive deficits reported in those at high risk of the disorder.
Although existing evidence supports an association between hypofrontality, depression and cognitive impairment, there is remaining uncertainty regarding the direction of the association between depressive symptoms and cognition. It should be noted however that in the high risk literature the abnormal prefrontal cortex response is most consistently reported as hyperfrontality (Callicott et al., 2003; Seidman et al., 2006). Such findings are often interpreted as a functional inefficiency of the region, or as a compensatory response to maintain adequate levels of performance (Fusar-Poli et al., 2007). In the current study however we report hypofrontality in the high risk subjects with depression. As in the established disorder, the directionality of response (hyper- or hypofrontality) is proposed to relate to perceived task difficulty and ensuing performance levels (the inverted ‘U’ see (Manoach, 2003)). We speculate that although no significant performance differences were found between the groups, these subjects consistently demonstrated the highest reaction times and highest (worse) word appropriateness scores at all levels of task difficulty, hence this pattern of decreased response may indicate the beginnings of a failure of response in these more symptomatic subjects. Increased task related activity in the superior temporal gyrus was also found in subjects at high risk of schizophrenia with depressive features. The prefrontal cortex and superior temporal gyrus have previously been shown to interact, with greater prefrontal activation leading to suppression of activity in the superior temporal gyrus (Lawrie et al., 2002). Increased superior temporal gyral activity has also been shown in subjects with depression who demonstrated a hypofrontal response to the Tower of London Task (Goethals et al., 2005). The authors of the study suggest that this response is compensatory for the dysfunction within the prefrontal cortex. In conclusion, dorsolateral prefrontal cortex dysfunction was associated with depressive features in this high risk cohort. Since we have previously reported elevated levels of depression in those who subsequently become ill, these findings may have potential relevance for the study of the early features of developing psychosis.
Role of funding source The study was funded by an MRC programme grant. Dr. Lawrie and Dr. Whalley are supported by a charitable donation from the Dr. Mortimer and Theresa Sackler Foundation. Dr. McIntosh is supported by the Health Foundation. Conflict of interest None of the authors have any conflicts of interest to declare.
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
Acknowledgement The study was funded by an MRC programme grant. Dr. Lawrie and Dr. Whalley are supported by a charitable donation from the Dr. Mortimer and Theresa Sackler Foundation. Dr. McIntosh is supported by the Health Foundation. Scanning was carried out at the Brain Imaging Research Centre (BIRC) for Scotland. Both BIRC and the Centre for Functional Imaging studies (CFIS) are funded by the Scottish Higher Education Funding Council (SHEFC). We would also like to thank those involved in subject recruitment, the radiographers, and the study participants. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jad.2007. 11.009. References an der Heiden, W., Könnecke, R., Maurer, K., Ropeter, D., Häfner, H., 2005. Depression in the long-term course of schizophrenia. European Archives of Psychiatry and Clinical Neuroscience 255, 174–184. Andreasen, N.C., O'Leary, D.S., Flaum, M., Nopoulos, P., Watkins, G.L., Boles Ponto, L.L., Hichwa, R.D., 1997. Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naive patients. Lancet 349, 1730–1734. Bloom, P.A., Fischler, I., 1980. Completion norms for 329 sentence contexts. Memory and Cogntion 8, 631–642. Bremner, J.D., Innis, R.B., Salomon, R.M., Staib, L.H., Ng, C.K., Miller, H.L., Bronen, R.A., Krystal, J.H., Duncan, J., Rich, D., Price, L.H., Malison, R., Dey, H., Soufer, R., Charney, D.S., 1997. Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. Archives of General Psychiatry 364–374. Callicott, J.H., Egan, M.F., Mattay, V.S., Bertolino, A., Bone, A.D., Verchinksi, B., Weinberger, D.R., 2003. Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. American Journal of Psychiatry 160, 709–719. Fitzgerald, P.B., Oxley, T.J., Laird, A.R., Kulkarni, J., Egan, G.F., Daskalakis, Z.J., 2006a. An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression. Psychiatry Research 148, 33–45. Fitzgerald, P.B., Oxley, T.J., Laird, A.R., Kulkarni, J., Egan, G.F., Daskalakis, Z.J., 2006b. An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression. Psychiatry Research 148, 33–45. Fusar-Poli, P., Perez, J., Broome, M., Borgwardt, S., Placentino, A., Caverzasi, E., Cortesi, M., Veggiotti, P., Politi, P., Barale, F., McGuire, P., 2007. Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews 31, 465–484. Glahn, D.C., Ragland, J.D., Abramoff, A., Barrett, J., Laird, A.R., Bearden, C.E., Velligan, D.I., 2005. Beyond hypofrontality:
105
a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Human Brain Mapping 25, 60–69. Goethals, I., Audenaert, K., Jacobs, F., Van de Wiele, C., Ham, H., Pyck, H., Vandierendonck, A., Van Heeringen, C., Dierckx, R., 2005. Blunted prefrontal perfusion in depressed patients performing the Tower of London task. Psychiatry Research 139, 31–40. Hashimoto, R., Numakawa, T., Ohnishi, T., Kumamaru, E., Yagasaki, Y., Ishimoto, T., Mori, T., Nemoto, K., Adachi, N., Izumi, A., Chiba, S., Noguchi, H., Suzuki, T., Iwata, N., Ozaki, N., Taguchi, T., Kamiya, A., Kosuga, A., Tatsumi, M., Kamijima, K., Weinberger, D.R., Sawa, A., Kunugi, H., 2006. Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Human molecular genetics 15, 3024–3033. Hodges, A., Byrne, M., Grant, E., Johnstone, E., 1999. People at risk of schizophrenia. Sample characteristics of the first 100 cases in the Edinburgh high-risk study. British Journal of Psychiatry 174, 547–553. Ingvar, D.H., Franzen, G., 1974. Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia. Acta Psychiatrica Scandinavica 50, 425–462. Johnstone, E.C., Abukmeil, S.S., Byrne, M., Clafferty, R., Grant, E., Hodges, A., Lawrie, S.M., Owens, D.G., 2000. Edinburgh high risk study—findings after four years: demographic, attainment and psychopathological issues. Schizophrenia Research 46, 1–15. Johnstone, E.C., Ebmeier, K.P., Miller, P., Owens, D.G., Lawrie, S.M., 2005. Predicting schizophrenia: findings from the Edinburgh highrisk study. British Journal of Psychiatry 186, 18–25. Lawrie, S.M., Buechel, C., Whalley, H.C., Frith, C.D., Friston, K.J., Johnstone, E.C., 2002. Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biological Psychiatry 51, 1008–1011. Manoach, D.S., 2003. Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophrenia Research 60, 285–298. Mayberg, H.S., Liotti, M., Brannan, S.K., McGinnis, S., Mahurin, R.K., Jerabek, P.A., Silva, J.A., Tekell, J.L., Martin, C.C., Lancaster, J.L., Fox, P.T., 1999. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. American Journal of Psychiatry 156, 675–682. Mayberg, H.S., Silva, J.A., Brannan, S.K., Tekell, J.L., Mahurin, R.K., McGinnis, S., Jerabek, P.A., 2002. The functional neuroanatomy of the placebo effect. American Journal of Psychiatry 159, 728–737. Medved, V., Petrovi, R., Igum, V., Szirovicza, L., Hotujac, L., 2001. Similarities in the pattern of regional brain dysfunction in negative schizophrenia and unipolar depression: a single photon emissioncomputed tomography and auditory evoked potentials study. Progress in Neuro Psychopharmacology and Biological Psychiatry 25, 993–1009. Menon, V., Anagnoson, R.T., Mathalon, D.H., Glover, G.H., Pfefferbaum, A., 2001. Functional neuroanatomy of auditory working memory in schizophrenia: relation to positive and negative symptoms. Neuroimage 13, 433–446. Merriam, E.P., Thase, M.E., Haas, G.L., Keshavan, M.S., Sweeney, J.A., 1999. Prefrontal cortical dysfunction in depression determined by Wisconsin card sorting test performance. American Journal of Psychiatry 156, 780–782. Owens, D.G.C., Miller, P., Lawrie, S.M., Johnstone, E.C., 2005. Pathogenesis of schizophrenia: a psychopathological perspective. British Journal of Psychiatry 186, 386–393. Perlstein, W.M., Carter, C.S., Noll, D.C., Cohen, J.D., 2001. Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. American Journal of Psychiatry 158, 1105–1113.
106
H.C. Whalley et al. / Journal of Affective Disorders 109 (2008) 99–106
Roberts, A.C., Robbins, T.W., Weiskrantz, L., 1998. The Prefrontal Cortex: Executive and Cognitive Functions. Oxford University Press. Seidman, L.J., Thermenos, H.W., Poldrack, R.A., Peace, N.K., Koch, J.K., Faraone, S.V., Tsuang, M.T., 2006. Altered brain activation in dorsolateral prefrontal cortex in adolescents and young adults at genetic risk for schizophrenia: an fMRI study of working memory. Schizophrenia Research 85, 58–72. Siegle, G.J., Thompson, W., Carter, C.S., Steinhauer, S.R., Thase, M.E., 2007. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biological Psychiatry 61, 198–209. St Clair, D., Blackwood, D., Muir, W., Carothers, A., Walker, M., Spowart, G., Gosden, C., Evans, H.J., 1990. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336, 13–16. Sweeney, J.A., Strojwas, M.H., Mann, J.J., Thase, M.E., 1998. Prefrontal and cerebellar abnormalities in major depression: evidence from oculomotor studies. Biological Psychiatry 43, 584–594. Thermenos, H.W., Seidman, L.J., Breiter, H., Goldstein, J.M., Goodman, J.M., Poldrack, R., Faraone, S.V., Tsuang, M.T., 2004. Functional magnetic resonance imaging during auditory verbal working memory in nonpsychotic relatives of persons with schizophrenia: a pilot study. Biological Psychiatry 55, 490–500.
Wassink, T.H., Flaum, M., Nopoulos, P., Andreasen, N.C., 1999. Prevalence of depressive symptoms early in the course of schizophrenia. American Journal of Psychiatry 315–316. Weinberger, D.R., Berman, K.F., 1996. Prefrontal function in schizophrenia: confounds and controversies. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 351, 1495–1503. Weinberger, D.R., Berman, K.F., Zec, R.F., 1986. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence.[see comment]. Archives of General Psychiatry 43, 114–124. Whalley, H.C., Simonotto, E., Flett, S., Marshall, I., Ebmeier, K.P., Owens, D.G., Goddard, N.H., Johnstone, E.C., Lawrie, S.M., 2004. fMRI correlates of state and trait effects in subjects at genetically enhanced risk of schizophrenia. Brain 127, 478–490. Whalley, H.C., Simonotto, E., Moorhead, T.W., McIntosh, A.M., Marshall, I., Owens, D.G.C., Goddard, N.H., Johnstone, E.C., Lawrie, S.M., 2006. Functional imaging as a predictor of schizophrenia. Biological Psychiatry 60, 454–462. Wing, J.K., Cooper, J.E., Sartorius, N., 1974. The Description and Classification of Psychiatric Symptoms. An Instruction Manual for the PSE and CATEGO Systems. Cambridge University Press, Cambridge.